The child with congenital toxoplasmosis.
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Child↗
Biomedical subjects
M Mets
Publications and source records attributed to M Mets.
Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness.
X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus. Two distinct clinical entities of X-linked CSNB have been proposed. Patients with complete CSNB show moderate to severe myopia, undetectable rod function and a normal cone response, whereas patients with incomplete CSNB show moderate myopia to hyperopia and subnormal but measurable rod and cone function. The electrophysiological and psychophysical features of these clinical entities suggest a defect in retinal neurotransmission. The apparent clinical heterogeneity in X-linked CSNB reflects the recently described genetic heterogeneity in which the locus for complete CSNB (CSNB1) was mapped to Xp11.4, and the locus for incomplete CSNB (CSNB2) was refined within Xp11.23 (ref. 5). A novel retina-specific gene mapping to the CSNB2 minimal region was characterized and found to have similarity to voltage-gated L-type calcium channel alpha1-subunit genes. Mutation analysis of this new alpha1-subunit gene, CACNA1F, in 20 families with incomplete CSNB revealed six different mutations that are all predicted to cause premature protein truncation. These findings establish that loss-of-function mutations in CACNA1F cause incomplete CSNB, making this disorder an example of a human channelopathy of the retina.
Amino Acid Sequence↗
Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study.
To assess the natural history of optic pathway tumors (OPT) in children with neurofibromatosis type 1 (NF-1), from January 1985 through May 1993 we performed a prospective, longitudinal study of OPT in an unselected population of children with NF-1. Of 227 children with NF-1 seen in a specialty clinic, 176 (77%) underwent neuroimaging. Children in whom tumors were identified were followed closely by both repeated neuroimaging and ophthalmologic examinations to detect tumor growth or visual deterioration. Thirty-three children (19%) were found to have OPT at a median age of 4.2 years. The median age of children who had ophthalmologic complaints was significantly lower than that of children who had no such complaints (1.9 vs 5.3 years; p < 0.001). Although eight tumors were discovered because of ophthalmologic complaints or evidence of precocious puberty, 25 children (76%) were free of symptoms at the time of diagnosis. Twenty-one children (64%) had normal ophthalmologic findings at diagnosis; six children, all with chiasmal tumors, had previously unrecognized decreased visual acuity. Only three children (9%) had evidence of either tumor growth or deteriorating vision after diagnosis; the median duration of neuroimaging follow-up was 2.4 years (range, 0.2 to 7.2 years) and of ophthalmologic examinations 3.4 years (range, 0.2 to 8.1 years). All symptomatic OPT were diagnosed before 6 years of age. We conclude that OPT rarely progress during the next few years in children with NF-1 once the OPT have been discovered. The utility of screening neuroimaging for OPT in symptom-free children with NF-1 appears very limited.
Adolescent↗
Early and longitudinal evaluations of treated infants and children and untreated historical patients with congenital toxoplasmosis: the Chicago Collaborative Treatment Trial.
Between December 1981 and May 1991, 44 infants and children with congenital toxoplasmosis were referred to our study group. A uniform approach to evaluation and therapy was developed and is described herein along with the clinical characteristics of these infants and children. In addition, case histories that illustrate especially important clinical features or previously undescribed findings are presented. Factors that contributed to the more severe disabilities included delayed diagnosis and initiation of therapy; prolonged, concomitant neonatal hypoxia and hypoglycemia; profound visual impairment; and prolonged, uncorrected increased intracranial pressure with hydrocephalus and compression of the brain. Years after therapy was discontinued, three children developed new retinal lesions (without loss of visual acuity when therapy for Toxoplasma gondii was initiated promptly), and three children experienced a new onset of afebrile seizures. Most remarkable were the normal developmental, neurological, and ophthalmologic findings at the early follow-up evaluations of many--but not all--of the treated children despite severe manifestations, such as substantial systemic disease, hydrocephalus, microcephalus, multiple intracranial calcifications, and extensive macular destruction detected at birth. These favorable outcomes contrast markedly with outcomes reported previously for children with congenital toxoplasmosis who were untreated or treated for only 1 month.
Animals↗
Absence of sensorineural hearing loss in treated infants and children with congenital toxoplasmosis.
Educationally significant hearing loss has been reported in 10% to 15% of children with congenital toxoplasmosis. As part of a pilot study to assess feasibility and safety of prolonged therapy for congenital toxoplasmosis, 30 congenitally infected infants and children were evaluated for auditory function. Serial testing, beginning within 2 months of birth, was performed. Availability of auditory brainstem response (ABR) testing made evaluation at an earlier age than previously possible. Six (20%) of the 30 infants had mild to moderate conductive type hearing loss associated with otitis media. No infant or child had sensorineural hearing loss. The better outcome we observed compared to previous reports of a 15% to 26% incidence of sensorineural hearing loss and 10% to 15% incidence of educationally significant, bilateral hearing impairment may be related to early initiation and/or prolonged institution of antimicrobial therapy. Continued followup to exclude progressive hearing impairment and study of larger numbers of children are needed to verify these preliminary findings.
Audiometry, Evoked Response↗
Phenotypes and functions of lymphocytes in congenital toxoplasmosis.
Comparisons of lymphocyte surface phenotypes and functions were made among 25 pediatric patients with congenital toxoplasmosis (ages 1 month to 5 years) and 24 uninfected babies, a baby with postnatally acquired infection, and 6 uninfected, 7 recently infected, and 6 chronically infected adults. Percentages of lymphocytes with B1, T11, T3, T4, T8, T6, B4, Ia, NKH phenotypes and T4 to T8 ratios of infected and uninfected babies were the same (p greater than 0.05). Lymphocytes from congenitally infected babies had lower blastogenic responses (mean stimulation index [SI] = 5) to Toxoplasma lysate antigens (TLA) than lymphocytes from adult control groups with recent and chronic infection (Mean SIs = 32, 72; p less than 0.001). Compared to infected adults, congenitally infected children had similar or greater responses to concanavalin A (mean SIs = 94; 118, 76, p greater than 0.05) and in mixed leukocyte culture (mean SIs = 63; 22, 26, p greater than 0.05). For symptomatic babies, low blastogenic response to TLA correlated with more severe disease at presentation (p = 0.002). Lymphocyte blastogenic responses to TLA were increased for most children when they were older than 15 months, but responses remained less than adult levels for 9 of the 17 older children studied. There was no correlation between concomitant serum pyrimethamine levels and lymphocyte blastogenic responses to TLA. Pyrimethamine and sulfonamide treatment in vitro and in vivo did not alter lymphocyte response to TLA. Lymphocytes from congenitally infected babies failed to produce either gamma interferon or Interleukin 2 when cultured with TLA. In contrast, they produced these lymphokines when cultured with concanavalin A or phytohemagglutinin. Specific deficits in cell-mediated immune responses to TLA may account for the significant organ damage that occurs in infants and children with congenital toxoplasmosis.
Adult↗
Assignment of the gene for complete X-linked congenital stationary night blindness (CSNB1) to Xp11.3.
X-linked congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder characterized by a presumptive defect of neurotransmission between the photoreceptor and bipolar cells. Carriers are not clinically detectable. A new classification for CSNB includes a complete type, which lacks rod function by electroretinography and dark adaptometry, and an incomplete type, which shows some rod function on scotopic testing. The refraction in the complete CSNB patients ranges from mild to severe myopia; the incomplete ranges from moderate hyperopia to moderate myopia. To map the gene responsible for this disease, we studied eight multigeneration families, seven with complete CSNB (CSNB1) and one with incomplete CSNB, by linkage analysis using 17 polymorphic X-chromosome markers. We found tight genetic linkage between CSNB1 and an Xp11.3 DNA polymorphic site, DXS7, in seven families with CSNB1 (LOD 7.35 at theta = 0). No recombinations to CSNB1 were found with marker loci DXS7 and DXS14. The result with DXS14 may be due to the small number of scored meioses (10). No linkage could be shown with Xq loci PGK, DXYS1, DXS52, and DXS15. Pairwise linkage analysis maps the gene for CSNB1 at Xp11.3 and suggests that the CSNB1 locus is distal to another Xp11 marker, TIMP, and proximal to the OTC locus. Five-point analysis on the eight families supported the order DXS7-CSNB1-TIMP-DXS225-DXS14. The odds in favor of this order were 9863:1. Removal of the family with incomplete CSNB (F21) revealed two most favored orders, DXS7-CSNB1-TIMP-DXS255-DXS14 and CSNB1-DXS7-TIMP-DXS255-DXS14. Heterogeneity testing using the CSNB1-M27 beta and CSNB1-TIMP linkage data (DXS7 was not informative in F21) was not significant to support evidence of genetic heterogeneity (P = 0.155 and 0.160, respectively).
Alleles↗
Contact lenses in the management of myopic anisometropic amblyopia.
We treated 16 patients aged 1 1/2 to 11 years with myopic anisometropic amblyopia with contact-lens correction of refractive error and occlusion. The degree of visual improvement compared favourably with that reported with the use of spectacles. There were no complications from contact lenses, and only one patient required anesthesia for fitting. Contact lenses appear to be more satisfactory than spectacle lenses in the management of myopic anisometropic amblyopia in regard to cosmesis, comfort, and treatment compliance. Patients with myelinated retinal nerve fibers and unilateral severe myopia had a poor visual prognosis. Treatment should not be abandoned in these children, but prolonged occlusion is not indicated. The presence of strabismus at the start of treatment appeared to have little effect on the final visual results. Most patients with strabismus responded well to occlusion, and all such children should be considered candidates for treatment of their amblyopia.
Amblyopia↗